Int J Med Sci 2020; 17(3):347-353. doi:10.7150/ijms.39823 This issue

Research Paper

Upregulation of Enzymes involved in ISGylation and Ubiquitination in patients with hepatocellular carcinoma

Hoang Van Tong1,2,✉, Nghiem Xuan Hoan3,4, Mai Thanh Binh3,4,5, Dao Thanh Quyen3,4, Christian G. Meyer4,5,6, Dinh Thi Thu Hang1, Dinh Thi Dieu Hang7, Ho Anh Son1,2, Hoang Van Luong1, Nghiem Duc Thuan1, Nguyen Truong Giang1, Do Quyet1, Mai Hong Bang3, Le Huu Song3,4, Thirumalaisamy P. Velavan4,5,6, Nguyen Linh Toan2

1. Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, Hanoi, Vietnam
2. Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
3. 108 Military Central Hospital, Hanoi, Vietnam
4. Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
5. Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
6. Duy Tan University, Da Nang, Vietnam
7. Hai Duong Medical Technical University, Hai Duong, Vietnam

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Tong HV, Hoan NX, Binh MT, Quyen DT, Meyer CG, Hang DTT, Hang DTD, Son HA, Van Luong H, Thuan ND, Giang NT, Quyet D, Bang MH, Song LH, Velavan TP, Toan NL. Upregulation of Enzymes involved in ISGylation and Ubiquitination in patients with hepatocellular carcinoma. Int J Med Sci 2020; 17(3):347-353. doi:10.7150/ijms.39823. Available from

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Background: ISGylation is the conjugation of ISG15 with target proteins. ISGylation occurs through an enzymatic cascade, which is similar to that of ubiquitination. Through ISGylation, ISG15 can bind to proteins involved in cell proliferation and differentiation, thus promoting genesis and progression of malignancies. The present study aims to investigate expression of genes involved in ISGylation and ubiquitination in patients with hepatocellular carcinoma and to correlate gene expression with clinical laboratory parameters of these patients.

Methods: mRNA expression of genes encoding enzymes involved in the ISGylation process (EFP, HERC5, UBA1, UBC and USP18) was evaluated by quantitative real-time PCR in 38 pairs of tumour and adjacent non-tumour tissues from patients with hepatocellular carcinoma and correlated with distinct clinical laboratory parameters.

Results: Relative mRNA expression of EFP, HERC5, UBA1 and USP18 was significantly higher in tumour tissues compared to adjacent non-tumour tissues (P=0.006; 0.012; 0.02 and 0.039, respectively). The correlation pattern of mRNA expression between genes in the tumours differed from the pattern in adjacent non-tumour tissues. Relative expression of EFP, HERC5 and UBA1 in adjacent non-tumour tissues was positively associated with direct bilirubin levels (Spearman's rho=0.31, 0.33 and 0.45; P=0.06, 0.05 and 0.01, respectively) and relative expression of USP18 in adjacent non-tumour tissues correlated negatively with ALT levels (Spearman's rho= -0.33, P=0.03).

Conclusions: EFP, HERC5, UBA1, and USP18 genes are upregulated in tumour tissues of patients with HCC and, thus, may be associated with the pathogenesis of hepatocellular carcinoma.

Keywords: hepatocellular carcinoma, Interferon-stimulated gene 15 (ISG15), ISGylation, E3 ligase, ubiquitin-specific protease 18 (USP18)